Recent work has implicated several signaling molecules that are known to be involved in the control of cell growth, differentiation, and apoptosis related to the regulation of Th2 differentiation and function. However, key questions concerning the interactions among these different signaling pathways and their relative importance in vivo remain unanswered. This proposal is based on our previous studies of atypical PKCs and p62 signaling pathways involved in Th2 differentiation. The Th2 polarization system is not only important from the point of view of asthma and other allergic diseases, but is also a very interesting paradigm of cell differentiation in which the crosstalk between different signaling pathways, including NF-?B and the Jak1/Stat6 cascade, are set in motion to ensure the efficiency and selectivity of the polarization pathways. Aberrations in Th2 differentiation lead to asthma, a chronic lung condition involving inflammation of the airways. Epidemiological studies demonstrate that there has been a worldwide increase in the prevalence of asthma since 1980, and that this disease affects about 15 million people in the US, of which 5 million are children. The long-term goal of the studies proposed here is to unravel the signaling cascades involved in Th2 differentiation, which will be critical in the control of allergic diseases, especially asthma. The overall objective of this proposal is to test the hypothesis that p62 and the aPKCs are essential players in these processes. Specifically, we will determine the role and mechanism of action of p62 in Th2 function, focusing on the pathways whereby p62 regulates the sustained phase of NF-?B activation during Th2 differentiation, as well as the potential role of PKC ?/??in this cascade. This will be addressed using mice with a "floxed" PKC ?/??gene, and in studies using p62- and PKC?-deficient mice and cells. Additionally, we will carry out studies to understand at a mechanistic level how PKC?, and potentially also PKC ?/? regulate Jak1 in the IL-4/Stat6 cascade. All the results from these ex vivo and in vitro studies will be validated in in vivo systems where we will assess the relevance of these molecules to asthma in a mouse model of allergic airway inflammation. This study will increase our understanding of the different mechanisms involved in the regulation of Th2 differentiation and asthma, and could also contribute to the development of novel and less toxic therapies for allergic pulmonary inflammation. Public Health Relevance Statement: Asthma is a chronic lung condition involving inflammation of the airways. It affects about 15 million people in the US, of which 5 million are children, and is considered to be the most common reason for childhood hospitalizations and school absenteeism. Epidemiological studies demonstrate that since 1980 there has been a worldwide increase in the prevalence of asthma. The pathology of asthma and other allergic diseases is associated with aberrant activation of CD4+ Th2 cells. Recent work has implicated several signaling molecules that are known to be involved in the control of cell growth, differentiation, and apoptosis in the regulation of Th2 differentiation and function. However, key questions concerning the interactions among these different signaling pathways and their relative importance in vivo remain unanswered. This study will increase our understanding of the different mechanisms involved in the regulation of Th2 differentiation and asthma, and would also contribute to the development of novel and less toxic therapies for allergic pulmonary inflammation.